By Helen Petousis Harris 21/02/2018 10

There exists a sustained brouhaha around the nature of the placebos used in the clinical trials for Gardasil.

The notion that some of the most rigorous vaccine trials ever conducted are questionable on account of their well thought out placebos is ill conceived at best. This is after over 270 million doses and huge epidemiological studies from all over the world comparing outcomes in vaccinated and unvaccinated (discussed ad nausea in my previous blogs). Guess what! Vaccinated have better outcomes than unvaccinated. Anyway, for the sake of anyone who is wondering about what all the placebo ruckus is about I have attempted to explain below.

What is a placebo?

A clinical placebo is a treatment that has no intended therapeutic effect. In a clinical trial a placebo could be a saline formulation which is typically inert when injected.  Or, the placebo could be the formulated mix of salts and left over impurities that are present with the vaccine under investigation minus the active ingredient (vaccine).

Vaccines often also have an extra added ingredient, called the adjuvant, which works as an immune enhancer.  The adjuvant is sometimes included in the placebo formulation.

Mind over matter is a very real phenomenon in medicine.

In using a placebo the investigators want to eliminate any thoughts, views, emotions and expectations as much as. Study participants will not know (they will be blind) to what treatment they receive, and often so will most of the investigators (double blind.

When you choose a non-active placebo

It has been well argued  that if there is an existing vaccine for a disease that it cannot be withheld from trial participants in order to test the new one against a placebo. That means if a new generation vaccine is developed for a disease, its effectiveness will need to be compared to its predecessor, and a placebo will not be needed. An example is the new Gardasil®9 vaccine. This new formulation contained nine instead of four different types of virus like particles. The pivotal trials compared the old and new vaccines head-to-head.

If you do not already have a vaccine against a disease then there is a case for using a placebo. An example of this was the first generation HPV vaccines. The formulated vaccine was put head to head with two different placebos. One was saline and the other the formulation mix minus the active ingredient.

What non-active placebo do you use?

There are two major considerations when choosing the placebo.

The placebo effect

The key objective of a placebo is to allow the participant to believe they have received the medicine being tested. In the case of an injectable vaccine the most common reaction is injection site pain, sometimes with minor redness and swelling. Often, the added adjuvant (immune enhancer) can be the main cause of the reaction and it is just doing its job. From a vaccinology perspective a mild to moderate injection site reaction is generally a good thing.

When you inject pure saline a very small proportion of recipients get sore arms where the injection was given.  A bigger proportion have a sore injection site when they get the placebo made from the formulation mix (missing the active vaccine). To make every injection as similar as possible in a vaccine study a good choice of placebo is the one that elicits an injection site reaction because the person is more likely to think they got the real deal.

If participants guess which group they are in (active versus placebo) then the study runs the risk of un-blinding. This can damage the integrity of the trial. Also, the investigators may guess which product is which just by looking at them. Simple differences like changes in smell, colour or viscosity could give it away.  It’s important that they appear identical to the investigator.

The role of the antigen

Another factor in placebo selection is the importance of understanding the role of the active ingredient (antigen or antibody generator). What difference to the reactogenicity and safety profile does the addition of the active ingredient play?

Many vaccine developers prefer to balance the safety profile (identified in the trial) by ensuring the products in the vaccine carrier are present in both the active and placebo products. This means both the active and placebo study arm should both have the same local reaction to the impurities and other ingredients such as buffers and adjuvants. Any additional reaction rates will be related to the active ingredient.

Some vaccine developers would prefer not to know if the active ingredient is the cause of the local reaction, and by not knowing can simply assert that they believe it is caused by the other ingredients and not by their antigen.

For a detailed list on vaccine ingredients and their function check out the Vaccine Ingredients resource from the Immunisation Advisory Centre.

The formulation without the active ingredient includes buffers, stabilisers and adjuvant. In the case of Gardasil there is sodium chloride (for tonicity), sodium borate (buffer), L-histidine (Stabiliser), polysorbate-80 (surfactant), and water for injection. When the active ingredient is added it is adsorbed to the adjuvant. One important question the investigators will want to answer is: What is the difference between a formulation that has just adjuvant and a formulation that has adjuvant adsorbed to active ingredient? Adsorbed means to adhere to via atoms, ion or molecules. In the case of vaccine adjuvant and antigen this is via the positive and negative charges on each (a positively charged antigen will require a negatively charged adjuvant).

Anyway, the choice of vaccine formulation minus the active ingredient as a placebo provides important data about the role of the active ingredient, which is the new kid on the block. Its behaviour when administered alone (without adjuvant in earlier phase studies) and in the full formulation is important.

Using the vaccine formulation mix minus the active ingredient is a normal practice in vaccine trials for the reasons outline above. For example, of three trials from different manufacturers for the same type of vaccine I am aware of, one used an adjuvant in the active formulation, and the adjuvant was not included in the placebo. Two of the three used the vaccine formulation mix in the placebo; the other trial used just saline as the placebo.

What was the placebo in the Gardasil trials?

There were two different placebos used. The one used in most of the controls included the vaccine formulation mix minus the active ingredient. A smaller group received saline with some impurities (L-histidine, polysorbate-80 and sodium borate). Therefore most of the participants who received a placebo would have had injection site reactions similar to the vaccine recipients, fulfilling the requirement of the placebo. Basically these placebos are stepwise progressions from the injection solution, injection solution with added adjuvant then the full formulation that included the antigen (active ingredient).

For a fuller discussion on the Gardasil placebos see my previous blog.

Arguments about the placebos – fact and logic

Some people argue that the Gardasil clinical trials are meaningless because:

  1. Most of the placebo recipients received the vaccine formulation minus the active ingredient and,
  2. The saline wasn’t really saline because it included L-histidine (an amino acid).

These arguments are factually and logically fallacious.

  • Fact: The placebos were true placebos by definition.
  • Arguing that the placebos contained adjuvant, therefore nullifying the study results, is logically flawed for the following reasons, among others:

First, just because a person imagines this is true does not make it true no matter how convinced they are. In know we live in a post truth world but I live in hope some people are still interested in objective evidence!

The burden of proof that there is a problem such as harm from using a non-saline placebo rests with those who claim it is harmful in the face of the wide body of evidence on vaccine safety. In other words it is a logical error to make a claim and assert people prove your negative (“prove these placebos are safe”) because you cannot prove a negative. This is otherwise known as evidence of absence. It is akin to proving that God does not exist, you cannot. You can only prove he does (away you go). It is up to the claimant to prove the claim that they are not safe. When you do this please do so with high quality epidemiological studies because that is the standard of proof required.

The fake placebo argument is a red herring and ignores all the evidence that supports the safety of both the vaccine and the adjuvant formulation. If you want to make an argument about the safety then you cannot ignore all the body of epidemiological data that support the safety in favour of ill-conceived laboratory studies. The premise that the various placebo formulations are unsafe is likely to be false, there is no data to remotely support this.
In arguing fake placebo-cover up-collusion-conspiracy I think the plaintiffs against HPV vaccine are running out of angles in the face of the tsunami of evidence in favour of safety but maybe I am just an optimist!

Many thanks to Nicole and Karin on this one.

10 Responses to “The brouhaha around placebo choice in vaccine trials”

  • The term placebo is clearly defined:

    It is a biologically inactive substance. Immunological adjuvants are not biologically inactive and they have known to be associated with serious side effects.

    They are by definition not placebos.
    A placebo (/pləˈsiːboʊ/ plə-SEE-boh; Latin placēbō, “I shall please”[1] from placeō, “I please”)[2][3] is a substance or treatment with no active therapeutic effect.
    A placebo (pluh-SEE-bow) is a substance or other kind of treatment that looks just like a regular treatment or medicine, but is not. It’s actually an inactive “look-alike” treatment or substance. This means it’s not a medicine.
    A placebo (or dummy pill) is an inert substance, typically a tablet, capsule or other dose form that does not contain an active drug ingredient.

    Using adjuvants for reasons of blinding is not a valid argument since drug safety studies are not required to use active placebos either. One could induce inflammation on the injection site by other means using various harmless substances(histamine), there is really no scientific reason to never use anything other than an adjuvant.

    The Gardasil trial had a saline group but in this group only mild side effects were measured making it impossible to measure serious adverse reactions.

    It is true that aluminum is everywhere around us including our food but aluminum particles in adjuvants are not the same as naturally occurring aluminum. They are metabolised in a different way, much of which is still poorly understood.

    see here:

    Proprietary formulations of aluminum particles without safety documentation can be used.

    As there is really no scientific reason for avoiding real placebos one has to conclude that the trial designs are used to make a product look safer than it is. A common practice in the pharmaceutical industry. Industry sponsored drug trials are often not 100% objective and honest and there is no reason to believe that commercial vaccine trials are any different.

    To learn more about dishonesty in for-profit science:

    • Skeptic
      You sat the term placebo is clearly defined, state it is a biologically inactive substance, then proceed to paste definitions that say no such thing. Do not confuse no therapeutic effect with biologically inactive. And, as Maurice has pointed out, I have explained this in the blog. I think it is fair to accept the general scientific consensus on the use of placebos in clinical studies because these are the standards that are globally accepted, adopted, and evaluated. This international consensus is arrived at by experience and reason.

      You are using fallacious arguments whereby you seem to be saying that anything that is not pure saline is not a true placebo because you have decided that that is the definition. This is a false premise. You then draw a false conclusion as you are saying therefore the vaccine is not safe. You have elected to ignore the huge body of evidence that shows vaccinated and unvaccinated are equally sick or healthy whichever way you want to look at it.

      Finally you use the strawman argument where you insinuate that i/we think industry sponsored drug trials are 100% objective. I/we hold no such position.

  • Skeptic

    A good analysis of “for-profit” attitudes is found in “Bad Pharma” by Ben Goldacre. I would recommend that you read it. I suspect that you won’t because it’s written by a real doctor.

    Medicine has been questioning the attitudes, motives and records of the pharmaceutical industry for decades; that questioning is not something new, even if it happens to be new to you.

    I would recommend that you follow up “Bad Pharma” with “Bad Science”, same author. It was written earlier but demonstrates how Big SCAM (Supplements, Complementary and Alternative Medicine) is even worse in it’s motives, attitudes and publication of records than Big Pharma.

    If you are a true sceptic, and not just trying to project a North American facade of one, you will know to apply your questions equally to all references and not just to cherry pick.

  • “I suspect that you won’t because it’s written by a real doctor.”

    Sweet shade dude. But what is your point? How is Dr Marcia Angell not a real doctor?

    Professor, was the saline trial part of the extra data that was submitted to the PBAC after its initial rejection?

    • Paul,
      Are you referring to the PBAC concerns about the cost of the Gardasil vaccine?

  • Skeptic/Paul,

    Problems with the pharmaceutical industry have been known by the medical establishment for many decades. Methods have been developed to reduce these problems and further methods are in development. The pharmaceutical industry has responded and there are currently less concerns than in the past although new concerns are arising.

    Angell appears to document some problems with the pharmaceutical industry and be shocked by them. It’s as though she hasn’t realised that others have been working on the problems for years if not decades.

    Goldacre, writing at least a decade later, documents the problems, the responses of the pharmaceutical industry, the changes made and their effects, and also proposes further methods to remove or minimise those problems, including options to prevent further problems developing. All duly referenced.

    Angell documents a problem. Goldacre documents past responses to the problem and their effects, reactions of the industry to those actions, further responses currently under way, and possible future actions by the medical and research establishments.

    As in the rest of science, it’s not good to cherry pick or to rely on outdated information. Multiple sources will give a more realistic viewpoint of where reality stands.

  • Professor. Cost-effectiveness, but yes. I went searching and from what I can glean from documents now no new clinical data was added, which is not my recollection. My apologies.

    Stuart mate, you do realise Skeptic and I are different people?

    Well since everyone’s recommending books, A Cup of Tea, A Bex and A Good Lie Down is a great read that taught me alot. Beware, its about 25 years old and written by a historian not a doctor. Feel free to link a better source on the subject if you know one.

    But to return to the subject at hand with a messy segue, one of the shiboleths that people trying to remove the APC’s from market faced, was arguments that its individual components were all known to be very safe for a long time. Not an exact analogy I know, but I am still failing to understand how adverse effects can be distinguished when the control uses an adjuvant. The argument that controls need to have a placebo that causes more adverse events so it can be an effective placebo to me seems counterproductive, cruel and unethical.

    What am I missing? Are there any reputable pro-vax PETA-like scientists that campaign for reform on this issue? I want to understand.

  • “Are there any reputable pro-vax PETA-like scientists…”

    PETA-like and Reputable are mutually exclusive conditions.

  • If you’re looking for books that might help you understand the perpetual ‘fussing’ over vaccines and vaccination, two I might recommend –

    Seth Mnookin’s exploration of the ‘vaccination debate’, The Panic Virus. I’ve reviewed it on Sciblogs here:

    If you want an (in-depth) look at the history of vaccines, you might try Arthur Allen’s book, Vaccine. The History of Vaccines website is another useful site. There are links to these two, and a few other sites, in my earlier Sciblogs articles, Immunisation then and now: